The candidate's long-term career goal is to become an independent investigator with interdisciplinary skills and expertise in dietary patterns, epidemiology, biomarkers and metabolomics, with a focus on cancer prevention and control. Several dietary patterns have been associated with colorectal cancer (CRC) risk but underlying mechanisms are not fully understood. Also, evidence is lacking on the consistency of dietary guidelines for overall health and CRC prevention given that it is not feasible to have an optimal diet for every disease. Furthermore, other biomarkers of diet, such as metabolomic profiling, have not been assessed with respect to CRC risk. Metabolomics is uniquely suited to assess metabolic responses to dietary stimuli, given that it is situated downstream to all the other ?omics?. Building on his prior work in hypothesis-driven dietary patterns and CRC prevention, the candidate seeks to fill these knowledge gaps by proposing to: 1) use a standardized methodology to compare the best diet for overall health with the best diet for CRC prevention, and further determine if any associations of dietary patterns with CRC prevention are mediated by mechanisms involving inflammation and insulin; 2) determine the inflammatory metabolome that intersects pathways due to inflammatory diets and circulating inflammatory markers, and evaluate the association of this unique metabolome with CRC risk; 3) determine the insulinemic metabolome that intersects pathways due to insulinemic diets and circulating insulin markers, and evaluate the association of the unique metabolome with CRC risk. To achieve these goals, the candidate and his mentors have designed a career development plan for research and educational training to: 1) help him develop expertise in dietary patterns research methods; 2) acquire skills in mediation analyses and 3) integrate and synthesize data from multiple sources including epidemiological, nutritional, and biological data. To achieve the proposed research aims, the candidate will utilize two large prospective cohort studies, the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), in which dietary and nondietary data have been collected every 2 to 4 years among 173,230 women and men over the last ?30 years, with ?3,400 CRC cases and ?43,800 all-cause deaths. Within these cohorts, a substantial number of participants donated blood samples that have been used to measure concentrations of several circulating inflammatory and insulin markers, and metabolites. This integrated interrogation of dietary patterns, biomarkers and metabolomics data will identify novel biomarkers for CRC early detection and prevention, and will improve the design of guidelines for healthful lifestyles that are optimized for CRC prevention. The interdisciplinary mentoring team will provide the requisite expertise to ensure the successful implementation of this K99/R00 proposal and the candidate's smooth transition to an independent investigator.